Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Patients With Influenza at High Risk of Influenza Complications

NCT02949011 | Completed Phase 3 Results DMC

• 2 other identifiers: 1602T08322016-002688-32
• Study Type: interventional
• Target: 2,184
• Locations: 0 countries
• Sites: N/A

Brief Summary

The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to improvement of influenza symptoms in patients with influenza presenting within 48 hours of symptom onset.

Conditions

Influenza

Keywords

Tamiflu®; Influenza; Oseltamivir; Flu; S-033188

Outcome Measures

Primary Outcomes (1)

• Time to Improvement of Influenza Symptoms

  Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Time to improvement of symptoms was defined as the time from the start of treatment to the time when all influenza symptoms were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience improvement of symptom s were censored at the last observation.

  From Day 1 pretreatment up to Day 14

Secondary Outcomes (20)

• Percentage of Participants With Positive Influenza Virus Titer at Each Time Point

  Days 2, 3, 4 (optional), 5, 6 (optional), and 9

• Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point

  Days 2, 3, 4 (optional), 5, 6 (optional), and 9.

• Change From Baseline in Virus Titer at Each Time Point

  Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9

• Change From Baseline in Virus RNA (RT-PCR) at Each Time Point

  Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9

• Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer

  Day 1 to Day 9

Study Arms (3)

Baloxavir Marboxil

EXPERIMENTAL

Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of \< 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5.

Drug: Baloxavir Marboxil; Drug: Placebo to Oseltamivir

Oseltamivir

ACTIVE COMPARATOR

Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.

Drug: Placebo to Baloxavir Marboxil; Drug: Oseltamivir

Placebo

PLACEBO COMPARATOR

Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.

Drug: Placebo to Baloxavir Marboxil; Drug: Placebo to Oseltamivir

Interventions

Baloxavir Marboxil DRUG

Tablets taken orally

Also known as: S-033188, Xofluza®

Baloxavir Marboxil

Placebo to Baloxavir Marboxil DRUG

Matching tablets taken orally

Oseltamivir; Placebo

Oseltamivir DRUG

Capsules taken orally

Also known as: Tamiflu®

Oseltamivir

Placebo to Oseltamivir DRUG

Matching placebo capsules taken orally

Baloxavir Marboxil; Placebo

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients or their legal guardians who provide written informed consent to participate in the study on a voluntary basis. For adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements.
• Male or female patients ≥ 12 years at the time of signing the informed consent/assent form.
• Patients with a diagnosis of influenza confirmed by all of the following:
• Fever ≥ 38ºC (axillary) during the predose examinations or within the 4 hours prior if antipyretics were taken
• At least 1 each of the following general and respiratory symptoms associated with influenza is present with a severity of moderate or greater:
• i. General symptoms (headache, feverishness or chills, muscle or joint pain, or fatigue) ii. Respiratory symptoms (cough, sore throat, or nasal congestion)
• The time interval between the onset of symptoms and the predose examinations is 48 hours or less. The onset of symptoms is defined as either:
• Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature)
• Time when the patient experiences at least 1 new general or respiratory symptom
• If a women of childbearing potential, agrees to use a highly effective method of contraception for 3 months after the first dose of study drug
• Asthma or chronic lung disease (such as chronic obstructive pulmonary disease or cystic fibrosis)
• Endocrine disorders (including diabetes mellitus)
• Residents of long-term care facilities (eg, nursing homes)
• Compromised immune system (including patients receiving corticosteroids not exceeding 20 mg of prednisolone or equivalent, and patients being treated for human immunodeficiency virus \[HIV\] infection with a CD4 count \> 350 cells/mm³ within the last 6 months)
• Neurological and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve, and muscle, eg, cerebral palsy, epilepsy \[seizure disorders\], stroke, muscular dystrophy, or spinal cord injury)

You may not qualify if:

• Patients with severe influenza virus infection requiring inpatient treatment.
• Patients with known allergy to oseltamivir (Tamiflu®).
• Patients unable to swallow tablets or capsules.
• Patients who have previously received baloxavir marboxil.
• Patients weighing ≤ 40 kg.
• Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations.
• Women who are pregnant, breastfeeding, or have a positive pregnancy test at the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test at the predose examinations:
• Postmenopausal women (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test)
• Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation
• Patients with concurrent infections at the predose examinations requiring systemic antimicrobial therapy.
• Patients with liver disease associated with hepatic impairment.
• Patients with cancer within the last 5 years (unless nonmelanoma skin cancer).
• Patients with untreated HIV infection or treated HIV infection with a CD4 count below 350 cells/mm3 in the last 6 months.
• Patients with immunosuppression following organ or bone marrow transplants.
• Patients exceeding 20 mg of prednisolone or equivalent dose of chronic systemic corticosteroids.

Sponsors & Collaborators

• Shionogi: lead

Related Publications (2)

• Retout S, De Buck S, Jolivet S, Duval V, Cosson V. A Pharmacokinetics-Time to Alleviation of Symptoms Model to Support Extrapolation of Baloxavir Marboxil Clinical Efficacy in Different Ethnic Groups with Influenza A or B. Clin Pharmacol Ther. 2022 Aug;112(2):372-381. doi: 10.1002/cpt.2648. Epub 2022 Jun 10.

  PMID: 35585696 DERIVED

• Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, Uehara T, Hayden FG. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020 Oct;20(10):1204-1214. doi: 10.1016/S1473-3099(20)30004-9. Epub 2020 Jun 8.

  PMID: 32526195 DERIVED

MeSH Terms

Conditions

Influenza, Human

Interventions

baloxavir; Oseltamivir

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons

Results Point of Contact

• Title: Shionogi Clinical Trials Administrator
• Organization: Shionogi Inc.

shionogiclintrials-admin@shionogi.co.jp

800-849-9707

Study Officials

• Shionogi Clinical Trials Administrator Clinical Support Help Line

  Shionogi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2016
• First Posted: October 31, 2016
• Study Start: January 11, 2017
• Primary Completion: April 12, 2018
• Study Completion: April 20, 2018
• Last Updated: November 19, 2019
• Results First Posted: November 6, 2019

Record last verified: 2019-11